Epidermal insulin/IGF-1 signalling control interfollicular morphogenesis and proliferative potential through Rac...

Area of Science:

• Dermatology
• Cell Biology
• Molecular Biology

Background:

• Epidermal self-renewal relies on progenitor cells with high proliferative capacity.
• Upstream signals governing epidermal progenitor potential are largely unknown.

Purpose of the Study:

• To investigate the roles of insulin and insulin-like growth factor receptors (IR and IGF-1R) in epidermal stem cell function.
• To elucidate the molecular mechanisms by which these receptors regulate epidermal proliferation and morphogenesis.

Main Methods:

• Utilized mouse models with epidermal-specific deletion of IR and/or IGF-1R.
• Assessed epidermal thickness, differentiation, apoptosis, and proliferation in vivo.
• Examined keratinocyte clonogenic capacity and keratin 15 expression ex vivo.
• Investigated the role of the small GTPase Rac in mediating receptor signaling.

Main Results:

• Deletion of IR and/or IGF-1R in the epidermis progressively reduced epidermal thickness.
• Clonogenic potential of keratinocytes lacking IR/IGF-1R was impaired, with reduced label-retaining cells and keratin 15 expression.
• The small GTPase Rac was identified as a key downstream target of IR/IGF-1R signaling.
• Activating Rac rescued the clonogenic defect and reversed epidermal thinning.

Conclusions:

• IR and IGF-1R signaling are essential for maintaining epidermal progenitor cell potential and interfollicular epidermal morphogenesis.
• The small GTPase Rac acts as a critical mediator of IR/IGF-1R function in epidermal stem cells.
• These findings reveal a novel signaling pathway crucial for lifelong skin renewal.